P1222: PACIFIC: BRENTUXIMAB VEDOTIN AND NIVOLUMAB ALONE AND THEN COMBINED WITH RITUXIMAB, CYCLOPHOSPHAMIDE, DOXORUBICIN AND PREDNISONE FOR UNTREATED PRIMARY MEDIASTINAL LARGE B-CELL LYMPHOMA PATIENTS
Authors: R. Steiner, P. Strati, C. Flowers, S. Neelapu, M. Green, L. Nastoupil, F. Hagemeister, L. Feng, S. Ahmed, R. Nair, L. Fayad, H. Lee, M. A. Rodriguez, J. Westin
Journal: HemaSphere (2022)

Background: Primary mediastinal large B-cell lymphoma (PMBL) is a rare subtype of aggressive B-cell lymphoma and affects primarily young adults. PMBL has a distinct genomic profile that has similarities to classic Hodgkin lymphoma with CD30 expression and genomic alterations in the programmed T-cell death-ligand 1. The trial CheckMate-436, including relapsed/refractory (rr) PMBL patients treated in at least 3rd line with nivolumab and brentuximab vedotin (BV) showed an overall response rate (ORR) of 73% and complete response rate (CRR) of 43% (Zinzani et al. JCO 2019). Although 70-94% of PMBL patients can be cured with frontline modality, the outcome of patients having rr-PMBL treated with intensive regimens is generally unfavorable. The discovery of novel frontline regimens to decrease chemoresistance and toxicities represents an urgent unmet clinical need for PMBL patients. Aims: We aim to evaluate the efficacy, safety, and quality of life of PMBL patients treated in the PACIFIC trial with BV and Nivolumab alone and then combined with Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (R-CHP). We hypothesize that BV+Nivolumab in the frontline setting will show an ORR at least as high as in the rr setting. Methods: The investigator-initiated trial PACIFIC (NCT04745949) is a phase II, open-label, single-center clinical trial for patients with previously untreated PMBL. Patients 18 years or older with untreated PMBL, stage I to stage IV disease are eligible. However, patients with an urgent need for systemic cytotoxic treatment will be excluded. Patients will start with an immune lead-in of BV (1.8 mg/Kg IV) and Nivolumab (240 mg flat dose IV) day 1 for cycles 1 and 2, in a 21-day cycle. During cycles 3 and 4, R-CHP will be added to BV-Nivolumab. Patients who have achieved complete response (CR) at PET/CT before cycle 5 will receive 2 more cycles of BV-Nivolumab+R-CHP (cycle 5 and 6) and BV-Nivolumab only for cycles 7 and 8. In case of CR on PET/CT after cycle 8, therapy will be considered completed. Patients in PR on PET/CT before cycle 5 will receive 4 more cycles of BV-Nivolumab+R-CHP (cycles 5-8). The primary endpoint is CRR at the end of therapy (EOT). The maximum sample size for the cohort is 40 patients, with a target CRR at EOT of 70%. The null hypothesis is that the true CRR at EOT is 50%, and the alternative hypothesis is that the true CRR at EOT is 70%. The Simon’s optimal two-stage design controls the one-sided type I error rate at 0.06 and yields the power of 0.8. Exploratory analyses include assessing molecular response by sequencing cell-free DNA and Multiplexed ion beam imaging to analyze the tumor microenvironment. Results: The trial is actively accruing at MD Anderson Cancer Center. To date, 2 out of 40 patients have been enrolled and are receiving therapy. Both patients (28 and 58 years old) presented a partial response (Lugano Classification) after 2 cycles of BV+Nivolumab, and one of them was evaluable after 2 cycles of BV-Nivolumab+R-CHP (cycles 3 and 4) with CR. Adverse events (AE) were similar to what is expected with the used drugs (nausea Grade 1 (n=1), fatigue Grade 1 (n=1), hypophosphatemia Grade 1 (n=1), hyperglycemia Grade 1 (n=1), leukocytosis Grade 1 (n=1), anemia Grade 1 (n=1)), including immune-related AE (fever Grade 1 (n=1), rash Grade 3 (n=1)). Image:Summary/Conclusion: The preliminary data of the PACIFIC trial with BV and Nivolumab alone and then combined with R-CHP are encouraging. Completion of this trial and further studies are needed to optimize frontline therapy of PMBL patients.